Molecular basis of hUHRF1 allosteric activation for synergistic histone modification binding by PI5P

dc.contributor.authorMandal, Papita
dc.contributor.authorEswara, Karthik
dc.contributor.authorYerkesh, Zhadyra
dc.contributor.authorKharchenko, Vladlena
dc.contributor.authorZandarashvili, Levani
dc.contributor.authorSzczepski, Kacper
dc.contributor.authorBensaddek, Dalila
dc.contributor.authorJaremko, Lukasz
dc.contributor.authorBlack, Ben E.
dc.contributor.authorFischle, Wolfgang
dc.contributor.departmentBiological and Environmental Science and Engineering (BESE) Division
dc.contributor.departmentBioscience
dc.contributor.departmentBioscience Program
dc.contributor.departmentCore Laboratories, King Abdullah University of Science and Technology (KAUST), Thuwal 23955, Kingdom of Saudi Arabia.
dc.contributor.departmentProteomics and Protein Expression
dc.contributor.departmentProteomics, protein expression & cytomet
dc.contributor.institutionDepartment of Biochemistry and Biophysics, Penn Center for Genome Integrity, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
dc.date.accessioned2022-08-25T13:37:18Z
dc.date.available2022-08-25T13:37:18Z
dc.date.issued2022-08-24
dc.description.abstractChromatin marks are recognized by distinct binding modules, many of which are embedded in multidomain proteins. How the different functionalities of such complex chromatin modulators are regulated is often unclear. Here, we delineated the interplay of the H3 amino terminus– and K9me-binding activities of the multidomain hUHRF1 protein. We show that the phosphoinositide PI5P interacts simultaneously with two distant flexible linker regions connecting distinct domains of hUHRF1. The binding is dependent on both, the polar head group, and the acyl part of the phospholipid and induces a conformational rearrangement juxtaposing the H3 amino terminus and K9me3 recognition modules of the protein. In consequence, the two features of the H3 tail are bound in a multivalent, synergistic manner. Our work highlights a previously unidentified molecular function for PI5P outside of the context of lipid mono- or bilayers and establishes a molecular paradigm for the allosteric regulation of complex, multidomain chromatin modulators by small cellular molecules.
dc.description.sponsorshipWe thank A. Aljahani for help with MST assays, S. Kreuz for scientific input during this study, and members of the Fischle laboratory for discussions. This work was supported by the King Abdullah University of Science and Technology (intramural funds and award OSR-2015-CRG-2616 of the KAUST Office of Sponsored Research to W.F.) and NIH grants R35GM130302 (to B.E.B.) and F32GM128265 (to L.Z.).
dc.eprint.versionPublisher's Version/PDF
dc.identifier.citationMandal, P., Eswara, K., Yerkesh, Z., Kharchenko, V., Zandarashvili, L., Szczepski, K., Bensaddek, D., Jaremko, Ł., Black, B. E., & Fischle, W. (2022). Molecular basis of hUHRF1 allosteric activation for synergistic histone modification binding by PI5P. Science Advances, 8(34). https://doi.org/10.1126/sciadv.abl9461
dc.identifier.doi10.1126/sciadv.abl9461
dc.identifier.issn2375-2548
dc.identifier.issue34
dc.identifier.journalScience Advances
dc.identifier.urihttp://hdl.handle.net/10754/680523
dc.identifier.volume8
dc.publisherAmerican Association for the Advancement of Science (AAAS)
dc.relation.urlhttps://www.science.org/doi/10.1126/sciadv.abl9461
dc.rightsArchived with thanks to Science Advances. © 2022. The Authors. This is an open access article under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleMolecular basis of hUHRF1 allosteric activation for synergistic histone modification binding by PI5P
dc.typeArticle
display.details.left<span><h5>License</h5>https://creativecommons.org/licenses/by/4.0/<br><br><h5>Type</h5>Article<br><br><h5>Authors</h5><a href="https://repository.kaust.edu.sa/search?query=orcid.id:0000-0003-4398-8971&spc.sf=dc.date.issued&spc.sd=DESC">Mandal, Papita</a> <a href="https://orcid.org/0000-0003-4398-8971" target="_blank"><img src="https://repository.kaust.edu.sa/server/api/core/bitstreams/82a625b4-ed4b-40c8-865a-d6a5225a26a4/content" width="16" height="16"/></a><br><a href="https://repository.kaust.edu.sa/search?query=orcid.id:0000-0001-7356-6361&spc.sf=dc.date.issued&spc.sd=DESC">Eswara, Karthik</a> <a href="https://orcid.org/0000-0001-7356-6361" target="_blank"><img src="https://repository.kaust.edu.sa/server/api/core/bitstreams/82a625b4-ed4b-40c8-865a-d6a5225a26a4/content" width="16" height="16"/></a><br><a href="https://repository.kaust.edu.sa/search?query=orcid.id:0000-0001-7124-1328&spc.sf=dc.date.issued&spc.sd=DESC">Yerkesh, Zhadyra</a> <a href="https://orcid.org/0000-0001-7124-1328" target="_blank"><img src="https://repository.kaust.edu.sa/server/api/core/bitstreams/82a625b4-ed4b-40c8-865a-d6a5225a26a4/content" width="16" height="16"/></a><br><a href="https://repository.kaust.edu.sa/search?query=orcid.id:0000-0003-4220-2412&spc.sf=dc.date.issued&spc.sd=DESC">Kharchenko, Vladlena</a> <a href="https://orcid.org/0000-0003-4220-2412" target="_blank"><img src="https://repository.kaust.edu.sa/server/api/core/bitstreams/82a625b4-ed4b-40c8-865a-d6a5225a26a4/content" width="16" height="16"/></a><br><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.author=Zandarashvili, Levani,equals">Zandarashvili, Levani</a><br><a href="https://repository.kaust.edu.sa/search?query=orcid.id:0000-0003-1038-3538&spc.sf=dc.date.issued&spc.sd=DESC">Szczepski, Kacper</a> <a href="https://orcid.org/0000-0003-1038-3538" target="_blank"><img src="https://repository.kaust.edu.sa/server/api/core/bitstreams/82a625b4-ed4b-40c8-865a-d6a5225a26a4/content" width="16" height="16"/></a><br><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.author=Bensaddek, Dalila,equals">Bensaddek, Dalila</a><br><a href="https://repository.kaust.edu.sa/search?query=orcid.id:0000-0001-7684-9359&spc.sf=dc.date.issued&spc.sd=DESC">Jaremko, Lukasz</a> <a href="https://orcid.org/0000-0001-7684-9359" target="_blank"><img src="https://repository.kaust.edu.sa/server/api/core/bitstreams/82a625b4-ed4b-40c8-865a-d6a5225a26a4/content" width="16" height="16"/></a><br><a href="https://repository.kaust.edu.sa/search?query=orcid.id:0000-0002-3707-9483&spc.sf=dc.date.issued&spc.sd=DESC">Black, Ben E.</a> <a href="https://orcid.org/0000-0002-3707-9483" target="_blank"><img src="https://repository.kaust.edu.sa/server/api/core/bitstreams/82a625b4-ed4b-40c8-865a-d6a5225a26a4/content" width="16" height="16"/></a><br><a href="https://repository.kaust.edu.sa/search?query=orcid.id:0000-0002-2335-8932&spc.sf=dc.date.issued&spc.sd=DESC">Fischle, Wolfgang</a> <a href="https://orcid.org/0000-0002-2335-8932" target="_blank"><img src="https://repository.kaust.edu.sa/server/api/core/bitstreams/82a625b4-ed4b-40c8-865a-d6a5225a26a4/content" width="16" height="16"/></a><br><br><h5>KAUST Department</h5><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.department=Biological and Environmental Science and Engineering (BESE) Division,equals">Biological and Environmental Science and Engineering (BESE) Division</a><br><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.department=Bioscience,equals">Bioscience</a><br><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.department=Bioscience Program,equals">Bioscience Program</a><br><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.department=Core Laboratories, King Abdullah University of Science and Technology (KAUST), Thuwal 23955, Kingdom of Saudi Arabia.,equals">Core Laboratories, King Abdullah University of Science and Technology (KAUST), Thuwal 23955, Kingdom of Saudi Arabia.</a><br><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.department=Proteomics and Protein Expression,equals">Proteomics and Protein Expression</a><br><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.department=Proteomics, protein expression & cytomet,equals">Proteomics, protein expression & cytomet</a><br><br><h5>KAUST Grant Number</h5>OSR-2015-CRG-2616<br><br><h5>Date</h5>2022-08-24</span>
display.details.right<span><h5>Abstract</h5>Chromatin marks are recognized by distinct binding modules, many of which are embedded in multidomain proteins. How the different functionalities of such complex chromatin modulators are regulated is often unclear. Here, we delineated the interplay of the H3 amino terminus– and K9me-binding activities of the multidomain hUHRF1 protein. We show that the phosphoinositide PI5P interacts simultaneously with two distant flexible linker regions connecting distinct domains of hUHRF1. The binding is dependent on both, the polar head group, and the acyl part of the phospholipid and induces a conformational rearrangement juxtaposing the H3 amino terminus and K9me3 recognition modules of the protein. In consequence, the two features of the H3 tail are bound in a multivalent, synergistic manner. Our work highlights a previously unidentified molecular function for PI5P outside of the context of lipid mono- or bilayers and establishes a molecular paradigm for the allosteric regulation of complex, multidomain chromatin modulators by small cellular molecules.<br><br><h5>Citation</h5>Mandal, P., Eswara, K., Yerkesh, Z., Kharchenko, V., Zandarashvili, L., Szczepski, K., Bensaddek, D., Jaremko, Ł., Black, B. E., & Fischle, W. (2022). Molecular basis of hUHRF1 allosteric activation for synergistic histone modification binding by PI5P. Science Advances, 8(34). https://doi.org/10.1126/sciadv.abl9461<br><br><h5>Acknowledgements</h5>We thank A. Aljahani for help with MST assays, S. Kreuz for scientific input during this study, and members of the Fischle laboratory for discussions. This work was supported by the King Abdullah University of Science and Technology (intramural funds and award OSR-2015-CRG-2616 of the KAUST Office of Sponsored Research to W.F.) and NIH grants R35GM130302 (to B.E.B.) and F32GM128265 (to L.Z.).<br><br><h5>Publisher</h5><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.publisher=American Association for the Advancement of Science (AAAS),equals">American Association for the Advancement of Science (AAAS)</a><br><br><h5>Journal</h5><a href="https://repository.kaust.edu.sa/search?spc.sf=dc.date.issued&spc.sd=DESC&f.journal=Science Advances,equals">Science Advances</a><br><br><h5>DOI</h5><a href="https://doi.org/10.1126/sciadv.abl9461">10.1126/sciadv.abl9461</a><br><br><h5>Additional Links</h5>https://www.science.org/doi/10.1126/sciadv.abl9461</span>
kaust.acknowledged.supportUnitOffice of Sponsored Research
kaust.acknowledged.supportUnitIntramural funds
kaust.grant.numberOSR-2015-CRG-2616
kaust.personMandal, Papita
kaust.personEswara, Karthik
kaust.personYerkesh, Zhadyra
kaust.personKharchenko, Vladlena
kaust.personSzczepski, Kacper
kaust.personBensaddek, Dalila
kaust.personJaremko, Lukasz
kaust.personFischle, Wolfgang
orcid.authorMandal, Papita::0000-0003-4398-8971
orcid.authorEswara, Karthik::0000-0001-7356-6361
orcid.authorYerkesh, Zhadyra::0000-0001-7124-1328
orcid.authorKharchenko, Vladlena::0000-0003-4220-2412
orcid.authorZandarashvili, Levani
orcid.authorSzczepski, Kacper::0000-0003-1038-3538
orcid.authorBensaddek, Dalila
orcid.authorJaremko, Lukasz::0000-0001-7684-9359
orcid.authorBlack, Ben E.::0000-0002-3707-9483
orcid.authorFischle, Wolfgang::0000-0002-2335-8932
orcid.id0000-0002-2335-8932
orcid.id0000-0002-3707-9483
orcid.id0000-0001-7684-9359
orcid.id0000-0003-1038-3538
orcid.id0000-0003-4220-2412
orcid.id0000-0001-7124-1328
orcid.id0000-0001-7356-6361
orcid.id0000-0003-4398-8971
refterms.dateFOA2022-08-25T13:38:02Z
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